Included as part of the "PRECAUTIONS" Section
Suicidal Thoughts And Behaviors In Children, Adolescents, And Young Adults
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of
their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes
in behavior, whether or not they are taking antidepressant medications, and this risk may persist until
significant remission occurs. Suicide is a known risk of depression and certain other psychiatric
disorders, and these disorders themselves are the strongest predictors of suicide. There has been a
long-standing concern, however, that antidepressants may have a role in inducing worsening of
depression and the emergence of suicidality in certain patients during the early phases of treatment.
Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others)
showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children,
adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other
psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with
antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants
compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive
compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9
antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults
with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2
months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of
suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs
studied. There were differences in absolute risk of suicidality across the different indications, with the
highest incidence in MDD. The risk of differences (drug vs placebo), however, were relatively stable
within age strata and across indications. These risk differences (drug-placebo difference in the number
of cases of suicidality per 1000 patients treated) are provided in Table 1.
||Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
||Increases Compared to Placebo
||14 additional cases
|18 to 24
||5 additional cases
||Decreases Compared to Placebo
|25 to 64
||1 fewer case
||6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the
number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.
However, there is substantial evidence from placebo-controlled maintenance trials in adults with
depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored
appropriately and observed closely for clinical worsening, suicidality, and unusual changes in
behavior, especially during the initial few months of a course of drug therapy, or at times of dose
changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been
reported in adult and pediatric patients being treated with antidepressants for major depressive disorder
as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the
emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal
impulses has not been established, there is concern that such symptoms may represent precursors to
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing
the medication, in patients whose depression is persistently worse, or who are experiencing emergent
suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if
these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is
feasible, but with recognition that discontinuation can be associated with certain symptoms [see DOSAGE AND ADMINISTRATION and Discontinuation Of Treatment With Irenka for descriptions of
the risks of discontinuation of Irenka].
Families and caregivers of patients being treated with antidepressants for major depressive
disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the
need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior,
and the other symptoms described above, as well as the emergence of suicidality, and to report
such symptoms immediately to health care providers. Such monitoring should include daily
observation by families and caregivers. Prescriptions for Irenka should be written for the
smallest quantity of capsules consistent with good patient management, in order to reduce the
risk of overdose.
Screening Patients For Bipolar Disorder
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed
(though not established in controlled trials) that treating such an episode with an antidepressant alone
may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar
disorder. Whether any of the symptoms described above represent such a conversion is unknown.
However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should
be adequately screened to determine if they are at risk for bipolar disorder; such screening should
include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and
depression. It should be noted that Irenka is not approved for use in treating bipolar depression.
There have been reports of hepatic failure, sometimes fatal, in patients treated with duloxetine. These
cases have presented as hepatitis with abdominal pain, hepatomegaly, and elevation of transaminase
levels to more than twenty times the upper limit of normal with or without jaundice, reflecting a mixed
or hepatocellular pattern of liver injury. Irenka should be discontinued in patients who develop jaundice
or other evidence of clinically significant liver dysfunction and should not be resumed unless another
cause can be established.
Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported.
Other postmarketing reports indicate that elevated transaminases, bilirubin, and alkaline phosphatase
have occurred in patients with chronic liver disease or cirrhosis.
Duloxetine increased the risk of elevation of serum transaminase levels in development program
clinical trials. Liver transaminase elevations resulted in the discontinuation of 0.3% (92/34,756) of
duloxetine-treated patients. In most patients, the median time to detection of the transaminase elevation
was about two months. In adult placebo-controlled trials in any indication, for patients with normal and
abnormal baseline ALT values, elevation of ALT >3 times the upper limit of normal occurred in 1.25%
(144/11,496) of duloxetine-treated patients compared to 0.45% (39/8716) of placebo-treated patients. In
adult placebo-controlled studies using a fixed dose design, there was evidence of a dose response
relationship for ALT and AST elevation of >3 times the upper limit of normal and >5 times the upper
limit of normal, respectively.
Because it is possible that Irenka and alcohol may interact to cause liver injury or that Irenka may
aggravate pre-existing liver disease, Irenka should not be prescribed to patients with substantial alcohol
use or evidence of chronic liver disease.
Orthostatic Hypotension, Falls And Syncope
Orthostatic hypotension, falls and syncope have been reported with therapeutic doses of duloxetine.
Syncope and orthostatic hypotension tend to occur within the first week of therapy but can occur at any
time during Irenka treatment, particularly after dose increases. The risk of falling appears to be related
to the degree of orthostatic decrease in blood pressure as well as other factors that may increase the
underlying risk of falls.
In an analysis of patients from all placebo-controlled trials, patients treated with duloxetine reported a
higher rate of falls compared to patients treated with placebo. Risk appears to be related to the presence
of orthostatic decrease in blood pressure. The risk of blood pressure decreases may be greater in
patients taking concomitant medications that induce orthostatic hypotension (such as antihypertensives)
or are potent CYP1A2 inhibitors [see Clinically Important Drug Interactions and DRUG INTERACTIONS] and in patients taking duloxetine at doses above 60 mg daily. Consideration
should be given to dose reduction or discontinuation of Irenka in patients who experience symptomatic
orthostatic hypotension, falls and/or syncope during Irenka therapy.
Risk of falling also appeared to be proportional to a patient's underlying risk for falls and appeared to
increase steadily with age. As elderly patients tend to have a higher underlying risk for falls due to a
higher prevalence of risk factors such as use of multiple medications, medical comorbidities and gait
disturbances, the impact of increasing age by itself is unclear. Falls with serious consequences
including bone fractures and hospitalizations have been reported [see ADVERSE REACTIONS
and PATIENT INFORMATION].
The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and
SSRIs, including duloxetine, alone but particularly with concomitant use of other serotonergic drugs
(including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St.
John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those
intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations,
delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness,
diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus,
hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting,
diarrhea). Patients should be monitored for the emergence of serotonin syndrome.
The concomitant use of Irenka with MAOIs intended to treat psychiatric disorders is contraindicated.
Irenka should also not be started in a patient who is being treated with MAOIs such as linezolid or
intravenous methylene blue. All reports with methylene blue that provided information on the route of
administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports
involved the administration of methylene blue by other routes (such as oral tablets or local tissue
injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with
an MAOI such as linezolid or intravenous methylene blue in a patient taking Irenka. Irenka should be
discontinued before initiating treatment with the MAOI [see DOSAGE AND ADMINISTRATION, and CONTRAINDICATIONS].
If concomitant use of Irenka with other serotonergic drugs including triptans, tricyclic antidepressants,
fentanyl, lithium, tramadol, buspirone, tryptophan and St. John's Wort is clinically warranted, patients
should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment
initiation and dose increases. Treatment with Irenka and any concomitant serotonergic agents, should be
discontinued immediately if the above events occur and supportive symptomatic treatment should be
SSRIs and SNRIs, including Irenka, may increase the risk of bleeding events. Concomitant use of
aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk.
Case reports and epidemiological studies (case-control and cohort design) have demonstrated an
association between use of drugs that interfere with serotonin reuptake and the occurrence of
gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from
ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of Irenka
and NSAIDs, aspirin, or other drugs that affect coagulation.
Severe Skin Reactions
Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur
with Irenka. The reporting rate of SJS associated with duloxetine use exceeds the general population
background incidence rate for this serious skin reaction (1 to 2 cases per million person years). The
reporting rate is generally accepted to be an underestimate due to underreporting.
Irenka should be discontinued at the first appearance of blisters, peeling rash, mucosal erosions, or any
other sign of hypersensitivity if no other etiology can be identified.
Discontinuation Of Treatment With Irenka
Discontinuation symptoms have been systematically evaluated in patients taking duloxetine. Following
abrupt or tapered discontinuation in adult placebo-controlled clinical trials, the following symptoms
occurred at 1% or greater and at a significantly higher rate in duloxetine-treated patients compared to
those discontinuing from placebo: dizziness, headache, nausea, diarrhea, paresthesia, irritability,
vomiting, insomnia, anxiety, hyperhidrosis, and fatigue.
During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there
have been spontaneous reports of adverse events occurring upon discontinuation of these drugs,
particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness,
sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion,
headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these
events are generally self-limiting, some have been reported to be severe.
Patients should be monitored for these symptoms when discontinuing treatment with Irenka. A gradual
reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable
symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming
the previously prescribed dose may be considered. Subsequently, the physician may continue
decreasing the dose but at a more gradual rate [see DOSAGE AND ADMINISTRATION].
Activation Of Mania/Hypomania
In adult placebo-controlled trials in patients with major depressive disorder, activation of mania or
hypomania was reported in 0.1% (4/3779) of duloxetine-treated patients and 0.04% (1/2536) of placebotreated
patients. No activation of mania or hypomania was reported in DPNP, GAD, or chronic
musculoskeletal pain placebo-controlled trials. Activation of mania or hypomania has been reported in a
small proportion of patients with mood disorders who were treated with other marketed drugs effective
in the treatment of major depressive disorder. As with these other agents, Irenka should be used
cautiously in patients with a history of mania.
The pupillary dilation that occurs following use of many antidepressant drugs including Irenka may
trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent
Duloxetine has not been systematically evaluated in patients with a seizure disorder, and such patients
were excluded from clinical studies. In adult placebo-controlled clinical trials, seizures/convulsions
occurred in 0.02% (3/12,722) of patients treated with duloxetine and 0.01% (1/9513) of patients treated
with placebo. Irenka should be prescribed with care in patients with a history of a seizure disorder.
Effect On Blood Pressure
In adult placebo-controlled clinical trials across indications from baseline to endpoint, duloxetine
treatment was associated with mean increases of 0.5 mm Hg in systolic blood pressure and 0.8 mm Hg
in diastolic blood pressure compared to mean decreases of 0.6 mm Hg systolic and 0.3 mm Hg diastolic
in placebo-treated patients. There was no significant difference in the frequency of sustained (3
consecutive visits) elevated blood pressure. In a clinical pharmacology study designed to evaluate the
effects of duloxetine on various parameters, including blood pressure at supratherapeutic doses with an
accelerated dose titration, there was evidence of increases in supine blood pressure at doses up to 200
mg twice daily. At the highest 200 mg twice daily dose, the increase in mean pulse rate was 5 to 6.8
beats and increases in mean blood pressure were 4.7 to 6.8 mm Hg (systolic) and 4.5 to 7 mm Hg
(diastolic) up to 12 hours after dosing.
Blood pressure should be measured prior to initiating treatment and periodically measured throughout
treatment [see ADVERSE REACTIONS].
Clinically Important Drug Interactions
Both CYP1A2 and CYP2D6 are responsible for Irenka metabolism.
Potential For Other Drugs To Affect Irenka
Co-administration of Irenka with potent CYP1A2 inhibitors should be avoided [see DRUG INTERACTIONS].
Because CYP2D6 is involved in Irenka metabolism, concomitant use of duloxetine with potent inhibitors
of CYP2D6 would be expected to, and does, result in higher concentrations (on average of 60%) of
Irenka [see DRUG INTERACTIONS].
Potential For Irenka To Affect Other Drugs
Drugs Metabolized by CYP2D6
Co-administration of Irenka with drugs that are extensively metabolized by CYP2D6 and that have a
narrow therapeutic index, including certain antidepressants (tricyclic antidepressants [TCAs], such as
nortriptyline, amitriptyline, and imipramine), phenothiazines and Type 1C antiarrhythmics (e.g.,
propafenone, flecainide), should be approached with caution. Plasma TCA concentrations may need to
be monitored and the dose of the TCA may need to be reduced if a TCA is co-administered with Irenka.
Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with
elevated plasma levels of thioridazine, Irenka and thioridazine should not be co-administered [see DRUG INTERACTIONS].
Other Clinically Important Drug Interactions
Use of Irenka concomitantly with heavy alcohol intake may be associated with severe liver injury. For
this reason, Irenka should not be prescribed for patients with substantial alcohol use [see Hepatotoxicity and DRUG INTERACTIONS].
CNS Acting Drugs
Given the primary CNS effects of Irenka, it should be used with caution when it is taken in combination
with or substituted for other centrally acting drugs, including those with a similar mechanism of action
[see Effect On Blood Pressure and DRUG INTERACTIONS].
Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Irenka. In many cases,
this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone
secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared
to be reversible when duloxetine was discontinued. Elderly patients may be at greater risk of
developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise
volume depleted may be at greater risk [see Use In Specific Populations]. Discontinuation
of Irenka should be considered in patients with symptomatic hyponatremia and appropriate medical
intervention should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment,
confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have
been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death.
Use In Patients With Concomitant Illness
Clinical experience with duloxetine in patients with concomitant systemic illnesses is limited. There is
no information on the effect that alterations in gastric motility may have on the stability of Irenka enteric
coating. In extremely acidic conditions, Irenka, unprotected by the enteric coating, may undergo
hydrolysis to form naphthol. Caution is advised in using Irenka in patients with conditions that may slow
gastric emptying (e.g., some diabetics).
Duloxetine has not been systematically evaluated in patients with a recent history of myocardial
infarction or unstable coronary artery disease. Patients with these diagnoses were generally excluded
from clinical studies during the product's premarketing testing.
Avoid use in patients with chronic liver disease or cirrhosis [see DOSAGE AND ADMINISTRATION, Hepatotoxicity, and Use In Specific Populations].
Severe Renal Impairment
Avoid use in patients with severe renal impairment, GFR <30 mL/min. Increased plasma concentration of
Irenka, and especially of its metabolites, occur in patients with end-stage renal disease (requiring
dialysis) [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].
Glycemic Control In Patients With Diabetes
As observed in DPNP trials, duloxetine treatment worsens glycemic control in some patients with
diabetes. In three clinical trials of duloxetine for the management of neuropathic pain associated with
diabetic peripheral neuropathy, the mean duration of diabetes was approximately 12 years, the mean
baseline fasting blood glucose was 176 mg/dL, and the mean baseline hemoglobin A1c (HbA1c) was
7.8%. In the 12-week acute treatment phase of these studies, duloxetine was associated with a small
increase in mean fasting blood glucose as compared to placebo. In the extension phase of these studies,
which lasted up to 52 weeks, mean fasting blood glucose increased by 12 mg/dL in the duloxetine group
and decreased by 11.5 mg/dL in the routine care group. HbA1c increased by 0.5% in the duloxetine and
by 0.2% in the routine care groups.
Urinary Hesitation And Retention
Irenka is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation
develop during treatment with Irenka, consideration should be given to the possibility that they might be
In post marketing experience, cases of urinary retention have been observed. In some instances of
urinary retention associated with duloxetine use, hospitalization and/or catheterization has been needed.
No specific laboratory tests are recommended.
Patient Counseling Information
See FDA-approved patient labeling (PATIENT INFORMATION).
Information On Medication Guide
Inform patients, their families, and their caregivers about the benefits and risks associated with treatment
with Irenka and counsel them in its appropriate use. A patient Medication Guide is available for Irenka. Instruct patients, their families, and their caregivers to read the Medication Guide before starting Irenka
and each time their prescription is renewed, and assist them in understanding its contents. Give patients
the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions
they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Advise patients of the following issues and ask them to alert their prescriber if these occur while taking
Suicidal Thoughts And Behaviors
Encourage patients, their families, and their caregivers to be alert to the emergence of anxiety,
agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia
(psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of
depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is
adjusted up or down.
Advise families and caregivers of patients to observe for the emergence of such symptoms on a day-today
basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or
health professional, especially if they are severe, abrupt in onset, or were not part of the patient's
presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal
thinking and behavior and indicate a need for very close monitoring and possibly changes in the
BOX WARNING, and WARNINGS AND PRECAUTIONS].
- Irenka should be swallowed whole and should not be chewed or crushed, nor should the capsule be
opened and its contents be sprinkled on food or mixed with liquids. All of these might affect the enteric
Continuing The Therapy Prescribed
While patients may notice improvement with Irenka therapy in 1 to 4 weeks, advise patients to continue
therapy as directed.
Inform patients that severe liver problems, sometimes fatal, have been reported in patients treated with
duloxetine. Instruct patients to talk to their healthcare provider if they develop itching, right upper belly
pain, dark urine, or yellow skin/eyes while taking Irenka, which may be signs of liver problems. Instruct
patients to talk to their healthcare provider about their alcohol consumption. Use of Irenka with heavy
alcohol intake may be associated with severe liver injury [see WARNINGS AND PRECAUTIONS].
Although Irenka does not increase the impairment of mental and motor skills caused by alcohol, use of
Irenka concomitantly with heavy alcohol intake may be associated with severe liver injury. For this
reason, Irenka should not be prescribed for patients with substantial alcohol use [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
Orthostatic Hypotension, Falls And Syncope
Advise patients of the risk of orthostatic hypotension, falls and syncope, especially during the period of
initial use and subsequent dose escalation, and in association with the use of concomitant drugs that
might potentiate the orthostatic effect of Irenka [see WARNINGS AND PRECAUTIONS].
Caution patients about the risk of serotonin syndrome with the concomitant use of Irenka and other
serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone,
tryptophan and St. John's Wort [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and DRUG INTERACTIONS].
Advise patients of the signs and symptoms associated with serotonin syndrome that may include mental
status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g.,
tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular
changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or
gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Caution patients to seek medical care
immediately if they experience these symptoms.
Caution patients about the concomitant use of Irenka and NSAIDs, aspirin, warfarin, or other drugs that
affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and
these agents has been associated with an increased risk of bleeding [see WARNINGS AND PRECAUTIONS].
Severe Skin Reactions
Caution patients that Irenka may cause serious skin reactions. This may need to be treated in a hospital
and may be life-threatening. Counsel patients to call their doctor right away or get emergency help if
they have skin blisters, peeling rash, sores in their mouth, hives, or any other allergic reactions [see WARNINGS AND PRECAUTIONS].
Discontinuation Of Treatment
Instruct patients that discontinuation of Irenka may be associated with symptoms such as dizziness,
headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and
fatigue, and should be advised not to alter their dosing regimen, or stop taking Irenka without consulting
their physician [see WARNINGS AND PRECAUTIONS].
Activation Of Mania Or Hypomania
Adequately screen patients with depressive symptoms for risk of bipolar disorder (e.g. family history
of suicide, bipolar disorder, and depression) prior to initiating treatment with Irenka. Advise patients to
report any signs or symptoms of a manic reaction such as greatly increased energy, severe trouble
sleeping, racing thoughts, reckless behavior, talking more or faster than usual, unusually grand ideas,
and excessive happiness or irritability [see WARNINGS AND PRECAUTIONS].
Advise patients that taking Irenka can cause mild pupillary dilation, which in susceptible individuals, can
lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle
glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with
iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to
be examined to determine whether they are susceptible to angle-closure, and have a prophylactic
procedure (e.g., iridectomy), if they are susceptible. [See WARNINGS AND PRECAUTIONS]
Advise patients to inform their physician if they have a history of seizure disorder [see WARNINGS AND PRECAUTIONS].
Effects On Blood Pressure
Caution patients that Irenka may cause an increase in blood pressure [see WARNINGS AND PRECAUTIONS].
Advise patients to inform their physicians if they are taking, or plan to take, any prescription or overthe-
counter medications, since there is a potential for interactions [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and DRUG INTERACTIONS].
Advise patients that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs,
including Irenka. Advise patients of the signs and symptoms of hyponatremia [see WARNINGS AND PRECAUTIONS].
- Advise patients to inform their physicians about all of their medical conditions [see WARNINGS AND PRECAUTIONS].
- Irenka is in a class of medicines that may affect urination. Instruct patients to consult with their
healthcare provider if they develop any problems with urine flow [see WARNINGS AND PRECAUTIONS].
Pregnancy And Nursing Mothers
Advise patients to notify their physician if they:
- become pregnant during therapy
- intend to become pregnant during therapy
- are nursing[see Use In Specific Populations]
Safety and efficacy of duloxetine in patients 7 to 17 years of age have been established for the treatment
of GAD. The types of adverse reactions observed with duloxetine in children and adolescents were
generally similar to those observed in adults. The safety and effectiveness of duloxetine have not been
established in pediatric patients less than 18 years of age with other indications. [See Use In Specific Populations].
Interference with Psychomotor Performance
Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies
duloxetine has not been shown to impair psychomotor performance, cognitive function, or memory, it
may be associated with sedation and dizziness. Therefore, caution patients about operating hazardous
machinery including automobiles, until they are reasonably certain that Irenka therapy does not affect
their ability to engage in such activities.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Duloxetine was administered in the diet to mice and rats for 2 years.
In female mice receiving duloxetine at 140 mg/kg/day (6 times the maximum recommended human dose
(MRHD) of 120 mg/day on a mg/m2 basis), there was an increased incidence of hepatocellular adenomas
and carcinomas. The no-effect dose was 50 mg/kg/day (2 times the MRHD) Tumor incidence was not
increased in male mice receiving duloxetine at doses up to 100 mg/kg/day (4 times the MRHD).
In rats, dietary doses of duloxetine up to 27 mg/kg/day in females (2 times the MRHD) and up to 36
mg/kg/day in males (3 times the MRHD) did not increase the incidence of tumors.
Duloxetine was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) and was not
clastogenic in an in vivo chromosomal aberration test in mouse bone marrow cells. Additionally,
duloxetine was not genotoxic in an in vitro mammalian forward gene mutation assay in mouse lymphoma
cells or in an in vitro unscheduled DNA synthesis (UDS) assay in primary rat hepatocytes, and did not
induce sister chromatid exchange in Chinese hamster bone marrow in vivo.
Impairment Of Fertility
Duloxetine administered orally to either male or female rats prior to and throughout mating at doses up
to 45 mg/kg/day (4 times the MRHD) did not alter mating or fertility.
Use In Specific Populations
Teratogenic Effects, Pregnancy Category C
There are no adequate and well-controlled studies of duloxetine administration in pregnant women. In
animal studies with duloxetine, fetal weights were decreased but there was no evidence of
teratogenicity in pregnant rats and rabbits at oral doses administered during the period of organogenesis
up to 4 and 7 times the maximum recommended human dose (MRHD) of 120 mg/day, respectively. When
duloxetine was administered orally to pregnant rats throughout gestation and lactation, pup weights at
birth and pup survival to 1 day postpartum were decreased at a dose 2 times the MRHD. At this dose,
pup behaviors consistent with increased reactivity, such as increased startle response to noise and
decreased habituation of locomotor activity were observed. Post-weaning growth was not adversely
affected. Irenka should be used in pregnancy only if the potential benefit justifies the potential risk to the
Fetal/Neonatal Adverse Reaction
Neonates exposed during pregnancy to serotonin - norepinephrine reuptake inhibitors (SNRIs) or
selective serotonin reuptake inhibitors (SSRIs) have developed complications requiring prolonged
hospitalization, respiratory support, and tube feeding which can arise immediately upon delivery.
Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature
instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor,
jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect
of the SNRIs or SSRIs, or possibly, a drug discontinuation syndrome. It should be noted that, in some
cases, the clinical picture is consistent with serotonin syndrome [see WARNINGS AND PRECAUTIONS].
In animal reproduction studies, duloxetine has been shown to have adverse effects on embryo/fetal and
When duloxetine was administered orally to pregnant rats and rabbits during the period of
organogenesis, there was no evidence of teratogenicity at doses up to 45 mg/kg/day (4 times the
maximum recommended human dose (MRHD) of 120 mg/day on a mg/m basis, in rat; 7 times the MRHD
in rabbit). However, fetal weights were decreased at this dose, with a no-effect dose of 10 mg/kg/day
approximately equal to the MRHD in rats; 2 times the MRHD in rabbits).
When duloxetine was administered orally to pregnant rats throughout gestation and lactation, the
survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were
decreased at a dose of 30 mg/kg/day (2 times the MRHD); the no-effect dose was 10 mg/kg/day.
Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise
and decreased habituation of locomotor activity, were observed in pups following maternal exposure to
30 mg/kg/day. Post-weaning growth and reproductive performance of the progeny were not affected
adversely by maternal duloxetine treatment.
Irenka is present in human milk. In a published study, lactating women who were weaning their infants
were given duloxetine. At steady state, the concentration of duloxetine in breast milk was approximately
25% that of maternal plasma. The estimated daily infant dose was approximately 0.14% of the maternal
dose. The developmental and health benefits of human milk feeding should be considered along with the
mother's clinical need for Irenka and any potential adverse effects on the milk-fed child from the drug or
from the underlying maternal condition. Exercise caution when Irenka is administered to a nursing
The disposition of duloxetine was studied in 6 lactating women who were at least 12 weeks postpartum
and had elected to wean their infants. The women were given 40 mg of duloxetine twice daily for 3.5
days. The peak concentration measured in breast milk occurred at a median of 3 hours after the dose.
The amount of duloxetine in breast milk was approximately 7 mcg/day while on that dose; the estimated
daily infant dose was approximately 2 mcg/kg/day. The presence of duloxetine metabolites in breast
milk was not examined.
Generalized Anxiety Disorder
In pediatric patients aged 7 to 17 years, efficacy was demonstrated in one 10-week, placebo-controlled
trial. The study included 272 pediatric patients with GAD of which 47% were 7 to 11 years of age.
Duloxetine demonstrated superiority over placebo as measured by greater improvement in the Pediatric
Anxiety Rating Scale (PARS) for GAD severity score [see Clinical Studies]. The safety and
effectiveness in pediatric patients less than 7 years of age have not been established.
Major Depressive Disorder
Efficacy was not demonstrated in two 10-week, placebo-controlled trials with 800 pediatric patients
with MDD, age 7 to 17. Neither duloxetine nor an active control (indicated for treatment of pediatric
depression) was superior to placebo. Thus, safety and effectiveness of duloxetine have not been
established in pediatric patients less than 18 years of age with MDD.
The most frequently observed adverse reactions in the clinical trials included nausea, headache,
decreased weight, and abdominal pain. Decreased appetite and weight loss have been observed in
association with the use of SSRIs and SNRIs. Perform regular monitoring of weight and growth in
children and adolescents treated with an SNRI such as duloxetine [see ADVERSE REACTIONS].
Use of Irenka in a child or adolescent must balance the potential risks with the clinical need [see BOX WARNING and WARNINGS AND PRECAUTIONS].
Duloxetine administration to young rats from post-natal day 21 (weaning) through post-natal day 90
(adult) resulted in decreased body weights that persisted into adulthood, but recovered when drug
treatment was discontinued; slightly delayed (~1.5 days) sexual maturation in females, without any effect
on fertility; and a delay in learning a complex task in adulthood, which was not observed after drug
treatment was discontinued. These effects were observed at the high dose of 45 mg/kg/day (2 times the
MRHD, for a child); the no-effect-level was 20 mg/kg/day (≈1 times the MRHD, for a child).
Of the 2,418 patients in premarketing clinical studies of duloxetine for MDD, 5.9% (143) were 65 years
of age or over. Of the 1041 patients in CLBP premarketing studies, 21.2% (221) were 65 years of age
or over. Of the 487 patients in OA premarketing studies, 40.5% (197) were 65 years of age or over. Of
the 1,074 patients in the DPNP premarketing studies, 33% (357) were 65 years of age or over. In the
MDD, GAD, and DPNP, OA, and CLBP studies, no overall differences in safety or effectiveness were
generally observed between these subjects and younger subjects, and other reported clinical experience
has not identified differences in responses between the elderly and younger patients, but greater
sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including duloxetine have
been associated with cases of clinically significant hyponatremia in elderly patients, who may be at
greater risk for this adverse event [see WARNINGS AND PRECAUTIONS].
In an analysis of data from all placebo-controlled-trials, patients treated with duloxetine reported a
higher rate of falls compared to patients treated with placebo. The increased risk appears to be
proportional to a patient's underlying risk for falls. Underlying risk appears to increase steadily with
age. As elderly patients tend to have a higher prevalence of risk factors for falls such as medications,
medical comorbidities and gait disturbances, the impact of increasing age by itself on falls during
treatment with duloxetine is unclear. Falls with serious consequences including bone fractures and
hospitalizations have been reported [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].
The pharmacokinetics of duloxetine after a single dose of 40 mg were compared in healthy elderly
females (65 to 77 years) and healthy middle-age females (32 to 50 years). There was no difference in
the Cmax, but the AUC of duloxetine was somewhat (about 25%) higher and the half-life about 4 hours
longer in the elderly females. Population pharmacokinetic analyses suggest that the typical values for
clearance decrease by approximately 1% for each year of age between 25 to 75 years of age; but age as
a predictive factor only accounts for a small percentage of between-patient variability. Dosage
adjustment based on the age of the patient is not necessary.
Duloxetine's half-life is similar in men and women. Dosage adjustment based on gender is not necessary.
Duloxetine bioavailability (AUC) appears to be reduced by about one-third in smokers. Dosage
modifications are not recommended for smokers.
No specific pharmacokinetic study was conducted to investigate the effects of race.
Patients with clinically evident hepatic impairment have decreased duloxetine metabolism and
elimination. After a single 20 mg dose of duloxetine, 6 cirrhotic patients with moderate liver impairment
(Child-Pugh Class B) had a mean plasma duloxetine clearance about 15% that of age- and gendermatched
healthy subjects, with a 5-fold increase in mean exposure (AUC). Although Cmax was similar
to normals in the cirrhotic patients, the half-life was about 3 times longer [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
Severe Renal Impairment
Limited data are available on the effects of duloxetine in patients with end-stage renal disease (ESRD).
After a single 60 mg dose of duloxetine, Cmax and AUC values were approximately 100% greater in
patients with end-stage renal disease receiving chronic intermittent hemodialysis than in subjects with
normal renal function. The elimination half-life, however, was similar in both groups. The AUCs of the
major circulating metabolites, 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine
sulfate, largely excreted in urine, were approximately 7- to 9-fold higher and would be expected to
increase further with multiple dosing. Population PK analyses suggest that mild to moderate degrees of
renal impairment (estimated CrCl 30 to 80 mL/min) have no significant effect on duloxetine apparent
clearance [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].